Biology subjects

Cesca, F.

Publications and source records attributed to Cesca, F..

4 recordsLinked to original sources

bioRxiv2023

Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis

In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs to proliferate. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair.

neuroscience↗

bioRxiv2021

A developmental stage- and Kidins220/ARMS-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

Astroglial cells are key to maintain nervous system homeostasis, as they are able to perceive a wide variety of extracellular signals and to transduce them into responses that may be protective or disruptive toward neighboring neurons through the activation of distinct signaling pathways. Neurotrophins are a family of growth factors known for their pleiotropic effects on neuronal survival, maturation and plasticity. In this work, we investigated: (i) the signaling competence of embryonic and postnatal primary cortical astrocytes exposed to brain-derived neurotrophic factor (BDNF); and (ii) the role of the scaffold protein Kinase D interacting substrate/ankyrin repeat-rich membrane spanning (Kidins220/ARMS), a transmembrane protein that mediates neurotrophin signaling in neurons, in the astrocyte response to BDNF. We found a shift from a kinase-based response in embryonic cells to a predominantly [Ca2+]i-based response in postnatal cultures associated with the decreased expression of the full-length BDNF receptor TrkB. We also found that Kidins220/ARMS contributes to the BDNF-activated intracellular signaling in astrocytes by potentiating both kinase and [Ca2+]i pathways. Finally, Kidins220/ARMS contributes to astrocytes homeostatic function by controlling the expression of the inwardly rectifying potassium channel (Kir) 4.1. Overall, our data contribute to the understanding of the complex role played by astrocytes within the central nervous system and identify Kidins220/ARMS as a novel actor in the increasing number of pathologies characterized by astrocytes dysfunctions.

neuroscience↗

bioRxiv2020

The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

Mecp2 deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturing Mecp2 null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects, in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment of Mecp2 null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an "early molecular phase" of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.

neuroscience↗

bioRxiv2019

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next generation sequencing (NGS) gene panel that has been transferred into clinical practice, replacing single disease gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

genetics↗